Alterations in the functional activity and/or number of serotonin2 (5-HT2) and/or serotonin1C (5-HT-1c) receptors have been implicated in the pathophysiology of a large number of mental illnesses including obsessive- compulsive disorder, schizophrenia, depression, anxiety, dysthymia, suicide, aggression and eating disorders. Additionally, a number of psycho- and neuropharmacologic agents including antidepressants (mianserin, amitriptyline, imipramine), antipsychotic drugs (loxapine, clozapine), hallucinogens (lysergic acid diethylamide) and anti-dysthymic agents (ritanserin) bind to 5-HT2 and 5-HT-1c receptors. Determining the precise roles the 5-HT2 and 5-HT-1c receptors have in mediating the effects of these agents is difficult because no truly subtype selective agents are currently available. Insights we gain in understanding how drugs bind to each of these receptors should enhance our ability to design novel receptor-specific agents which can be used to treat mental illnesses. This proposal will determine how agonists and antagonists bind to 5-HT2 and 5-HT-1c receptors. We will utilize the techniques of molecular biology and receptor pharmacology to identify specific amino acids essential for specifying the ligand binding domains of each receptor. We are utilizing four major techniques. (1) chimeric protein construction (2) site directed mutagenesis, (3) molecular modelling and (4) structural biochemical measurements. Our strategy is to test three-dimensional molecular models of 5- HT2 and 5- HT-1c receptor-ligand interactions using a combination of molecular biological and structural-biochemical techniques. We will also take advantage of unique mutations we have produced to probe the molecular details responsible for hallucinogen- induced alterations of serotonin receptors in vitro. These findings will be useful for the design and synthesis of new medications to treat psychiatric diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH057635-06
Application #
2891025
Study Section
Special Emphasis Panel (ZMH1-NRB-A (04))
Program Officer
Brady, Linda S
Project Start
1994-07-01
Project End
2001-06-30
Budget Start
1999-07-01
Budget End
2000-06-30
Support Year
6
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Case Western Reserve University
Department
Psychiatry
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
Davies, Marilyn A; Conley, Yvette; Roth, Bryan L (2011) Functional SNPs in genes encoding the 5-HT2A receptor modify the affinity and potency of several atypical antipsychotic drugs. Biol Res Nurs 13:55-60
Jensen, Niels H; Rodriguiz, Ramona M; Caron, Marc G et al. (2008) N-desalkylquetiapine, a potent norepinephrine reuptake inhibitor and partial 5-HT1A agonist, as a putative mediator of quetiapine's antidepressant activity. Neuropsychopharmacology 33:2303-12
Dewkar, Gajanan K; Peddi, Srinivas; Mosier, Philip D et al. (2008) Methoxy-substituted 9-aminomethyl-9,10-dihydroanthracene (AMDA) derivatives exhibit differential binding affinities at the 5-HT(2A) receptor. Bioorg Med Chem Lett 18:5268-71
Dukat, Malgorzata; Mosier, Philip D; Kolanos, Renata et al. (2008) Binding of serotonin and N1-benzenesulfonyltryptamine-related analogs at human 5-HT6 serotonin receptors: receptor modeling studies. J Med Chem 51:603-11
Allen, John A; Yadav, Prem N; Roth, Bryan L (2008) Insights into the regulation of 5-HT2A serotonin receptors by scaffolding proteins and kinases. Neuropharmacology 55:961-8
Gray, John A; Roth, Bryan L (2007) Molecular targets for treating cognitive dysfunction in schizophrenia. Schizophr Bull 33:1100-19
Armbruster, Blaine N; Li, Xiang; Pausch, Mark H et al. (2007) Evolving the lock to fit the key to create a family of G protein-coupled receptors potently activated by an inert ligand. Proc Natl Acad Sci U S A 104:5163-8
Davies, M A; Setola, V; Strachan, R T et al. (2006) Pharmacologic analysis of non-synonymous coding h5-HT2A SNPs reveals alterations in atypical antipsychotic and agonist efficacies. Pharmacogenomics J 6:42-51
Roth, Bryan L; Kroeze, Wesley K (2006) Screening the receptorome yields validated molecular targets for drug discovery. Curr Pharm Des 12:1785-95
Strachan, Ryan T; Ferrara, Gina; Roth, Bryan L (2006) Screening the receptorome: an efficient approach for drug discovery and target validation. Drug Discov Today 11:708-16

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